The newly arising field of AllergoOncology is based upon observations and studies showing that those individuals with raised levels of IgE (e.g. individuals who suffer from allergies) are much less likely to suffer from certain types of cancer. Researchers in this field are exploring the therapeutic potential of the IgE antibody class in the prevention and treatment of certain cancers, under the premise that redirected immune pathways developed as adaptive responses to microbial/parasitic infection might be directed against malignancy.
IgE antibodies mediate allergic and asthmatic reactions, characterized by immediate hypersensitivity, followed by an inflammatory delayed type response requiring the recruitment of effector cells. The uniqueness of the allergic reaction is due to the presence of mast cells and Langerhans/dendritic cells in the tissue that are sensitized by the IgE bound to the high-affinity FcεRI (Kinet, J P, Annu. Rev. Immunol., 17: 931-72: 931-972 (1999); and Ravetch J V, and Kinet J P, Annu. Rev. Immunol., 9: 457-492 (1991)). The activated Langerhans/dendritic cells migrate to local lymph nodes and stimulate cognate T cells, which migrate to the tissue, participate in the inflammatory response and stimulate antibody synthesis. IgE bound to mast cells and basophils can cause degranulation of the cells, but it requires cross-linking by the antigen the IgE recognizes. Following the acute phase of recruitment, eosinophils are recruited in the late-phase reaction. Activated eosinophils are strong mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) via toxic granule proteins and cause tissue damage via pro-inflammatory cytokines and vasoactive lipid mediators (leukotrienes, prostaglandin D2, platelet-activating factor). The processing of the IgE containing immune complexes by Langerhans cells and dendritic cells is a critical step for the induction of the late-phase reaction. Activated T helper cells generate IL-4 and IL-5, which in turn recruits and activates eosinophils causing ADCC and antibody-dependent cell-mediated phagocytosis (ADCP) (Kinet, J P, Annu. Rev. Immunol., 17:931-72.:931-972 (1999); Maurer, D., et al., J. Immunol., 161: 2731-2739 (1998) and Maurer D., et al., J. Immunol., 154: 6285-6290 (1995)).
While B cells can recognize antigen in its native conformation, T cells generally recognize antigen that has been “processed” by antigen presenting cells and then presented on the surface of the cell by major histocompatibility complex (MHC) molecules (Peakman, M. and Vergani, D., New York: Churchhill Livingston; (1997)). MHC molecules are receptors for peptide antigens. There are two classes of MHC molecules, termed MHC class I and MHC class II. Although united in their function of peptide antigen presentation and contact points for T cells, the differences in the structure and intracellular trafficking of the two types are critical because among other things, they elicit very different immune responses. A major obstacle in the creation of effective tumor immunity is that typically, there is poor presentation of tumor antigen on MHC class I and class II molecules together (cross-presentation). Dendritic cells are bone marrow-derived leukocytes that are more potent initiators of T cell-dependent immune responses than any other antigen presenting cells that have been tested (Peakman, M. and Vergani, D., New York: Churchill Livingston; (1997)). Unlike other antigen presenting cells, dendritic cells can acquire antigens from their environment and process them for cross-presentation, allowing activation of both CD8+ and CD4+ T cells. However, this process requires high antigen concentrations. Simultaneous presentation on MHC II provides for T helper cell activation. Depending on the stimuli, either production of cytokines IL-12 and IFN-γ by T helper (Th) cell 1 type and cytotoxic T lymphocytes (CTL) induction occurs (collectively referred to herein as the “Th1/Tc1 immune response”) or IL-4, IL-5 and IL-10 is produced by Th2 cells for B cell help (referred to herein as “Th2 immune response”). An important factor in immune induction is the activation or maturation of the antigen presenting cells, which induces the expression of co-stimulatory molecules that are necessary to engage the T cell.
It is now believed that the engagement of the toll-like receptor (TLR) family (Okamoto, M. and Sato, M., J. Med. Invest., 50: 9-24 (2003)) as well as other receptors including Fc receptors (Hamano, Y., et al., J. Immunol., 164: 6113-6119 (2000) and Regnault, A., et al., The Journal of Experimental Medicine, 189: 371-380 (1999)) mediates activation and maturation of macrophages and dendritic cells, which is crucial for activating the innate immune system. Fc receptors have also been shown to facilitate antigen uptake and presentation. Researchers have shown that immune complex pulsed DC induce stronger CD4− and CD8+ T cell responses as compared to DC pulsed with PSA alone (Berlyn, K A, et al., Clin. Immunol., 101: 276-283 (2001)). Similarly, NY-ESO-1 as well as ovalbumin or pyruvate dehydrogenase are all presented to T cells much more efficiently when captured as an immune complexes rather than as free-antigen (Regnault A., et al., The Journal of Experimental Medicine 189:371-380 (1999); Nagata Y., et al., Proc. Natl. Acad. Sci. U.S.A., 99: 10629-10634 (2002); Kita, H., et al., J. Exp. Med., 195:113-123 (2002) and Schuurhuis, D H, et al., J. Immunol., 168: 2240-2246 (2002)). The results suggest that effective cancer vaccines may be generated by administering antibodies that target circulating antigen and form immune complexes that target DC in vivo. The role of IgE as a component of an immune complex in altering antigen presentation is less understood and is believed to contribute to the aggravation and perpetuation of the atopic response to allergen as demonstrated in the IgE mediated influence enhancing Th2 (IL-4, IL-10) T cells responses to allergen. (Maurer et al, JI 161:2731-2739, 1998). The art has not addressed non-atopic responses.
IgE binds to two types of Fc receptors, called FcεRI (or high-affinity FcεR) (Ka=1011 M−1) and FcεRII (or low-affinity FcεR, CD23) (Ka<108 M−1). Therefore, unlike antibodies of the IgG class, IgE binds to its FcR with extremely high affinity which in the case of FcεRI is about three orders of magnitude higher than that of IgG for the FcRs (FcγRI-III) and in the case of FcεRII is as high as that of IgG for its high affinity FcγRI (Gould, H J, et al., Annu. Rev. Immunol., 21: 579-628. Epub@2001 December@19.:579-628 (2003); Gounni, A S, et al., Nature, 367: 183-186 (1994); Kinet, J P, Annu. Rev. Immunol., 17: 931-72:931-972 (1999) and Ravetch J V, and Kinet J P, Annu. Rev. Immunol., 9: 457-492 (1991)). Because the IgE concentration in normal serum is usually very low (less than 1 μg/mL), the FcεR are typically available for occupancy if IgE is induced by allergies and parasitic infestation or if administered. The FcεRI is composed of four polypeptide chains, one α, one β, and two γ chains. The a chain contains the IgE binding site and is a member of the immunoglobulin supergene family. The FcεRII consists of one polypeptide chain which shows homology to animal lectin receptors. FcεRI is expressed on mast cells and basophils as well as Langerhans cells and dendritic cells where it is involved in antigen presentation, on eosinophils where it plays a role in defense against parasitic infection, and also on monocytes (see Kinet, J P, Annu. Rev. Immunol., 17: 931-72.:931-972 (1999) for a review). Crosslinking of the FcεRI induces immediate release of mediators of inflammation such as histamine, leukotrienes, prostaglandin E2, or β-glucuronidase and delayed secretion of IL-4, 5, and 6. FcεRII is a member of the Ig superfamily, more widely expressed on resting and mature B cells, monocytes, follicular dendritic cells, macrophages, eosinophils, platelets, Langerhans cells, and a subset of T cells (10-15% of tonsillar T cells). IL-4 up-regulates FcεRII expression on B cells and macrophages. FcεRII on macrophages, eosinophils, and platelets mediates ADCC to schistosomules, enhance phagocytosis, and induce the release of granule enzymes (Gounni, A S, et al., Nature, 367: 183-186 (1994); Kinet, J P, Annu. Rev. Immunol., 17: 931-72.:931-972 (1999) and Spiegelberg, H L., J. Invest. Dermatol., 94: 49S-52S (1990)). FcεRII is involved in both IgE regulation and allergen presentation by B-cells, but understanding the functional roles of CD23 is further complicated by the fact that it exists both as a cell surface molecule and in a soluble form generated by cleavage from the cell surface; furthermore, it exists in both monomeric and oligomeric states (see Gould, H J, and Sutton, B J, Nat. Rev. Immunol., 8: 205-217 (2008) for a review). CD23 responds to high levels of IgE by downregulating IgE secretion. In human monocytes, CD23 triggering results in release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, IL-1, IL-6, and granulocyte/macrophage-colony stimulating factor (GM-CSF). IL-4 appears to play a central role in immediate-type hypersensitivity. It induces human B cells to secrete IgE and IgG4 and activated T helper cells. IL-4 also stimulates mast cell growth and up-regulates FcεRII expression.
Most of the antibodies used in the treatment of cancer, including FDA approved antibodies such as trastuzumab (HERCEPTIN®) and rituximab (RITUXAN®), are of the IgG class (Carter, P., IBC's Tenth International Conference. 6-9 Dec. 1999, La Jolla, Calif., USA. IDrugs, 3: 259-261 (2000); Carter, P., Nat. Rev. Cancer, 1: 118-129 (2001) and Carter, P J, Nat. Rev. Immunol., 6: 343-357 (2006)). However, monoclonal IgE antibodies specific for tumor antigens have been reported. The application of IgE for the therapy of cancer was pioneered by Nagy et al. (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)), who developed a murine IgE monoclonal antibody specific for the major envelope glycoprotein (gp36) of mouse mammary tumor virus (MMTV) and demonstrated significant anti-tumor activity in C3H/HeJ mice bearing a syngeneic MMTV-secreting mammary adenocarcinoma (H2712) (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)). Kershaw et al. (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)) developed a murine monoclonal IgE named 30.6, specific for an antigenic determinant expressed on the surface of colorectal adenocarcinoma cells. Mouse IgE 30.6 inhibited the growth of established human colorectal carcinoma COLO 205 cells growing subcutaneously in severe combined immune deficient (SCID) mice, although this effect was transient. By contrast, a mouse IgG 30.6 and a mouse/human chimeric IgE 30.6 did not show anti-tumor effects. The mouse IgE specific effect was attributed to the interaction of the antibody with FcεR bearing effector cells since the activity was specifically abrogated by prior administration of a nonspecific mouse IgE (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)). The lack of effect exhibited by the mouse/human chimeric IgE 30.6 is explained by the fact that mouse FcεRI binds mouse IgE, but not human IgE. Gould et al. (Gould, H J, et al., Eur. J. Immunol., 29: 3527-3537 (1999)) developed a mouse/human chimeric IgE (MOv18-IgE) and IgG MOv18 (IgG1) specific for the ovarian cancer tumor-associated antigen folate binding protein (FBP). The protective activities of MOv18-IgE and MOv18-IgG1 were compared in a SCID mouse xenograft model of human ovarian carcinoma (IGROV1). Mice were reconstituted with human peripheral blood mononuclear cells (PBMC) to provide the model with effector cells capable of binding human IgE constant regions. The beneficial effects of MOv18-IgE were greater and of longer duration than those of MOv18-IgG1 demonstrating the superior anti-tumor effects of IgE antibodies (Gould, H J, et al., Eur. J. Immunol., 29: 3527-3537 (1999)). In addition, the group of Gould et al. recently demonstrated for the first time monocyte-mediated IgE-dependent tumor cell killing by two distinct pathways, ADCC and phagocytosis (ADCP), mediated through FcεRI and FcεRII (Karagiannis, S N, et al., Cancer Immunol. Immunother., 57: 247-263 (2008) and Karagiannis, S N, et al., J. Immunol., 179: 2832-2843 (2007)). This group has also used this assay system to assess preliminary bioactivity of an anti-Her2 IgE construct, (Karragiannis P., Cancer Immunol. and Immunother. 2008 epub ahead of print). Since human PBMC are short-lived in SCID mice it is expected that the anti-tumor effect will be enhanced in humans where the supply of effector cells would be permanent. None of the studies could address the capacity of the mouse/human chimeric IgE to elicit an adaptive immune response due to the fact that murine APCs such as Dendritic cells do not express the FcεRI (Kinet, J P, Annu. Rev. Immunol., 17: 931-72.:931-972 (1999)).
Relevant epidemiological studies on the association of allergic diseases with cancer support a lower risk of cancer among people with a history of allergies or high levels of serum IgE including different hematopoietic malignancies (Grulich, A E and Vajdic, C M, Pathology, 37: 409-419 (2005); Wang, H. and Diepgen, T L, Allergy, 60: 1098-1111 (2005); Grulich, A E, et al., Cancer Epidemiol. Biomarkers Prev., 16: 405-408 (2007); Turner, M C, et al., Am. J. Epidemiol., 162: 212-221 (2005); Wang, H. and Diepgen, T L, Br., J. Dermatol., 154: 205-210 (2006); Wang, H., et al., Int. J. Cancer, 119: 695-701 (2006); Turner, M C, et al., Int. J. Cancer, 118: 3124-3132 (2006) and Melbye, M., et al., J. Natl. Cancer Inst., 99: 158-166 (2007)) and solid tumors such as ovarian, colorectal, pancreatic cancer, and glioma (Wang, H. and Diepgen, T L, Allergy, 60: 1098-1111 (2005); Turner, M C, et al., Am. J. Epidemiol., 162: 212-221 (2005); Wang, H., et al., Int. J. Cancer, 119: 695-701 (2006); Turner, M C, et al., Int. J. Cancer, 118: 3124-3132 (2006); Mills, P K, et al., Am. J. Epidemiol., 136: 287-295 (1992); Wiemels, J L, et al., Cancer Res., 64: 8468-8473 (2004) and Wrensch, M., et al., Cancer Res., 66: 4531-4541 (2006)).
Furthermore, mice infested with nematodes are resistant to syngeneic mammary adenocarcinoma and show lower incidence of spontaneous mammary tumors (Ogilvie, B M, et al., Lancet., 1: 678-680 (1971) and Weatherly, N F, J. Parasitol., 56: 748-752 (1970)). Eosinophilia, either in peripheral blood or tumor-associated tissue, is frequently associated with some tumor types and also found after immunotherapy with IL-2, IL-4, GM-CSF, and antibody to CTLA-4 (Lotfi, R, et al., J. Immunother., 30: 16-28 (2007)). Within several tumor types including gastrointestinal tumors, this observation is associated with a significantly better prognosis, whereas their presence in rejecting allografts is largely seen as a harbinger of poor outcome (Lotfi, R. and Lotze, M T, J. Leukoc. Biol., 83: 456-460 (2008)). Matta et al. (Clin Cancer Res., 13:5348-5354 (2007)) have reported that multiple myeloma patients with relatively higher IgE levels had a better survival than patients with lower levels of IgE. Importantly, this is clearly reflected on the levels of IgE and not the other classes of immunoglobulins. These studies are consistent with a natural role of IgE in the immunosurveillance of cancer including multiple myeloma. Fu, et al. (Clin Exp Immunol, 153:401-409, 2008) demonstrated that antibodies of the IgE class isolated from pancreatic cancer patients mediate antibody-dependent cell-mediated cytotoxicity (ADCC) against cancer cells. Finally, treatment with omalizumab (XOLAIR®), which decreases free IgE in serum and down-regulates IgE receptors in effector cells to dampen IgE-mediated inflammatory response, appears to lead to a higher chance of developing cancer. Approximately 1 in 200 treated asthmatic patients developed breast, prostate, melanoma, non-melanoma skin, or parotid gland malignancies during the median observation period of 1 year while in the control group the incidence was 1 in 500 (Dodig, S., et al., Acta Pharm., 55: 123-138 (2005)). These studies suggest a natural role of IgE in the immunosurveillance of cancer with an estimated 186,320 new cases in the U.S. for 2008, prostate cancer is the most frequently diagnosed cancer (25% of all cancers) in men. Prostate cancer is the second leading cause of cancer deaths in American men, accounting for 10% (28,660 cases) of all cancer-related deaths. For reasons that remain unclear, incidence rates are significantly higher in African American men than in white men and death rates remain more than twice as high as those in white men (Jemal, A., et al., CA Cancer J. Clin., 58: 71-96 (2008); Cancer Facts & Figures. American Cancer Society (2008) and Cancer Facts and Figures for African Americans 2007-2008. American Cancer Society, 2008). According to the most recent data, the lifetime probability of developing prostate cancer is 1 in 6. Over the past 25 years, the 5-year survival rate for all stages combined has increased from 69% to almost 99% and relative 10-year and 15-year survival is 91% and 76%, respectively. The dramatic improvements in survival, particularly at 5 years, are mainly attributable to earlier diagnosis (Cancer Facts & Figures, American Cancer Society (2008)). As a result of the high survival rates, many patients die “with” their disease rather than “from” their disease, albeit following years of invasive therapies.
The high frequency of intercurrent mortality as opposed to prostate cancer-specific mortality, and the morbidity of currently available treatments for asymptomatic individuals, has led some groups to propose a less interventional or deferred-therapy approach for early-stage disease (Cancer Facts & Figures, American Cancer Society (2008)). More controversial is the management of tumors with adverse features such as a positive margin, vascular invasion, or capsular penetration. Most urologists and radiation oncologists, however, do not recommend additional therapy if the PSA is undetectable. If PSA persists, and depending on the findings at surgery, the probability that the patient has subclinical micrometastatic disease is high (DeVita, V T, et al., Cancer—principles and practice of oncology (1997)). Clearly there is a need for an effective, yet relatively benign treatment for men with possible minimum disease (i.e., an effective cancer vaccine or immunotherapy). For patients with metastatic disease or persistence of PSA, which account for approximately 15% of patients (Cancer Facts & Figures, American Cancer Society (2008)), androgen ablation through surgical or pharmaceutical approaches often controls malignancy for extended periods; however, adverse effects are significant, and ultimately, prostate cancer becomes hormone refractory. Chemotherapy and palliative radiotherapies can help with patient management, but cannot cure this condition.
Prostate cancer is associated with two well characterized and highly specific antigens, prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA). PSA is a particularly attractive target antigen for immunotherapy because this 33-kDa protein (serine protease) is almost exclusively synthesized within the prostate gland and found circulating in human serum. PSA can also be identified in the cytoplasmic compartment of prostate epithelium and prostate tumor cells and is released into the tumor microenvironment. The increasing serum levels of PSA associated with the development of prostate cancer make it both a useful marker for disease progression as well as a promising target for immunotherapy, particularly T cell mediated immunotherapy (Zhang, S., et al., Clin. Cancer Res., 4: 295-302 (1998)). High levels of PSA are found in the tumor (Katzenwadel, A. et al., Anticancer Res., 20: 1551-1555 (2000); Sinha, A A, et al., Anticancer Res., 19: 893-902 (1999); Sinha, A A, et al., Anat. Rec., 245: 652-661 (1996) and Mirochnik, Y., et al., Drug Deliv., 11: 161-167 (2004)). Vaccination in both humans (Roos, A K, et al., Prostate, 62: 217-223 (2005) and mice (Pavlenko, M., et al., Br. J. Cancer, 91: 688-694 (2004)) with DNA encoding PSA has demonstrated specific immunity as measured by PSA-specific cytotoxic T lymphocytes (CTLs). In addition, this approach was protective when mice were challenged with PSA-expressing tumors. Additionally, in a phase II clinical trial investigating the immunogenicity of autologous DC pulsed with human recombinant PSA, specific immunity was generated in several patients as demonstrated by the presence of PSA-specific T cells detected by enzyme-linked immunoSPOT (ELISPOT) (Barrou, B., et al., Cancer Immunol. Immunother., 53: 453-460 (2004)).
Given the profound medical impact of prostate cancer (28,660 expected deaths from prostate cancer for 2008), the relatively high mortality rate for African American men, and the lack of adequate therapies for men with refractory metastatic disease, there is a need to develop innovative modalities of treatment in this indication.